Calcium activation of cAMP and MAP kinase (MAPK) signaling is required for consolidation of hippocampus- dependent memories and also plays a pivotal role in other forms of neuroplasticity including long-lasting, long- term potentiation (L-LTP). This project focuses on mechanisms by which Ca2+ regulates MAPK and adenylyl cyclase during memory formation and the role of MAPK oscillations for the persistence of hippocampus-dependent memory. This proposal is based upon several discoveries made by our lab during the last funding period including the finding that SCOP, a neurospecific protein, attenuates MAPK activity and CRE-mediated transcription in hippocampal neurons. Furthermore, we discovered that SCOP is proteolyzed by calpain, a calcium-stimulated protease, during memory formation. We found that over expression of SCOP in the hippocampus blocks consolidation of memory for novel objects, without affecting acquisition or short-term memory. We hypothesize that calcium-stimulated degradation of SCOP may play an important role in other forms of neuroplasticity including spatial memory and L-LTP. We also discovered that MAPK, PKA, and MSK-1, a CREB kinase, are coactivated in the same subset of neurons in the area CA1 of the hippocampus during memory formation and that these signaling events are not stimulated during training in mice lacking calcium-stimulated adenylyl cyclases (AC1 and AC8). Despite evidence supporting a role for cAMP, MAPK, and CREB-mediated transcription in memory consolidation, this hypothesis does not readily explain the duration of LTM which can persist well beyond the lifetime of gene products increased during memory formation. Therefore, we examined MAPK activity in the hippocampus over extended periods of time to determine if the pathway undergoes periodic reactivation. We discovered that cAMP, as well as MEK and MAPK activities undergo a circadian oscillation in the hippocampus. We hypothesize that the persistence of contextual fear memory may depend upon the circadian oscillation of this signaling pathway. PUBLIC HEALTH RELEVANCE: Memory loss is associated with a number of human diseases including Alzheimer's disease and is generally associated with aging. This project focuses on molecular mechanisms underlying memory consolidation and persistence. Consequently, this research may identify new drug target sites that can be exploited to enhance long-term and short-term memory.